The central objective of this proposal is to build 3D models of two epithelial cancers, lung and breast, which together cause more than 200,000 deaths each year in the U.S alone. The models will be used for 1- comparative analysis of how organ-specificity is maintained, a fundamental property that bears direct relevance to cancer progression and metastasis; 2- determining whether responses to targeted therapies are organ-specific; and if so, 3- which components of the organ microenvironment may be causally involved in organ-specificity and therapeutic response. We hypothesize that inflammatory mediators, from immune cells as well as from resident myoepithelial, endothelial and activated stromal cells, contribute to tumor aggressiveness and resistance to targeted therapies. We will develop and utilize new biomaterials, substrata, defined media and markers for inclusion of immune, endothelial and normal- and cancer-derived stromal cells. This proposal brings together experts in cell, molecular and cancer biology and includes lung and breast oncologists, and investigators with expertise in imaging, tumor immunology, bioengineering, nanotechnology, materials science and computation. The 3 projects are as follows: I- To develop conditions for defining and maintaining endothelial cell phenotypes specific to normal and malignant breast and lung, and to define organ-specific responses of endothelial cells to models developed in II and III. II- To develop a 3D model for normal and malignant human bronchial epithelium, and to test the influence of inflammatory mediators. IIITo build on the existing 3D models of the breast epithelium by incorporating other cell types and the effect of inflammatory microenvironments. All projects will test a number of targeted therapeutics, some of which are new and provided by our collaborators. Data quality control will be ensured since all projects will work through a virtual core to standardize cell culture and reagent development, and validate measurements of markers' and cellular responses. The creation of a physiological milieu will aid in understanding how these two different organs respond to, and interact with, their respective microenvironments. Moreover, elucidating similarities and differences in breast and airway epithelium will facilitate discovery and design of novel tissuespecific therapies.